ABSTRACT Lung cancer is the leading cause of cancer-related death in the U.S., accounting for 142,670 deaths in 2019. Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancers (NSCLC). Inflammatory monocyte (IM) infiltration in LUSC is associated with higher mortality. Using LUSC mouse models developed in our lab, we found that CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Preliminary RNA-seq data from our LUSC mouse models identify Spon1 upregulation in tumor bearing IMs compared to IMs from healthy mice. Spon1 is an axonal guidance molecule for the developing nervous system. Thus, I propose that neuronal axons are recruited into the tumor by IMs. Studies in prostate cancer have demonstrated that patients with increased innervation have increased cancer growth and metastasis and poor prognosis. While studies have shown worse prognosis with increased nerve recruitment, the mechanisms of recruitment are unclear. Given that Spon1 is associated with tissue remodeling and innervation, and that tumor neurogenesis mediates metastasis through neuronal axons, we hypothesize that (i) IMs release SPON1 into the TME and (ii) SPON1 drives LUSC metastasis through the recruitment of neuronal axons to the tumor. I propose to test this hypothesis through the following aims: 1.) Determine the role of SPON1+ IMs on recruitment of axons into the TME. 2.) Determine the role of SPON1+ IMs have on LUSC tumor progression and metastasis. This project will create an important intersection between two valuable disciplines to study how IMs, a component of the immune system, may be recruiting neuronal axons into the tumor to drive LUSC metastasis and disease progression. This understanding will then lend way for the development of targeted therapeutics against SPON1, IMs or specific classes of neurons within the tumor. This project has the potential to create a meaningful impact for patients by opening the door to multiple therapeutic targets. Furthermore, I believe this project and my comprehensive training plan will prepare me for a successful career by starting me on the F-to-K-to-R pipeline of an independently funded physician-scientist.